scholarly journals PET Tracers for Imaging Cardiac Function in Cardio-oncology

Author(s):  
James M. Kelly ◽  
John W. Babich

Abstract Purpose of Review Successful treatment of cancer can be hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. This risk can be mitigated if the injury to the heart is detected before the onset to irreversible cardiac impairment. The gold standard for cardiac imaging in cardio-oncology is echocardiography. Despite improvements in the application of this modality, it is not typically sensitive to sub-clinical or early-stage dysfunction. We identify in this review some emerging tracers for detecting incipient cardiotoxicity by positron emission tomography (PET). Recent Findings Vectors labeled with positron-emitting radionuclides (e.g., carbon-11, fluorine-18, gallium-68) are now available to study cardiac function, metabolism, and tissue repair in preclinical models. Many of these probes are highly sensitive to early damage, thereby potentially addressing the limitations of current imaging approaches, and show promise in preliminary clinical evaluations. Summary The overlapping pathophysiology between cardiotoxicity and heart failure significantly expands the number of imaging tools available to cardio-oncology. This is highlighted by the emergence of radiolabeled probes targeting fibroblast activation protein (FAP) for sensitive detection of dysregulated healing process that underpins adverse cardiac remodeling. The growth of PET scanner technology also creates an opportunity for a renaissance in metabolic imaging in cardio-oncology research.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Fouad Zouein ◽  
Carlos Zgheib ◽  
John Fuseler ◽  
John E Hall ◽  
Mazen Kurdi ◽  
...  

How hypertension causes heart failure is not known. Since patients with heart failure have reduced cardiac STAT3 and STAT3 KO mice develop heart failure with age, we tested the hypothesis that reduced STAT3 transcriptional activity contributes at an early stage to remodeling that precedes heart failure in hypertension using SA mice with a STAT3 S727A mutation. SA and wild type (WT) mice received angiotensin (A) II (1000 ng/kg/min) or saline (S) for 17 days. Hearts of WT and SA mice had similar levels of STAT3-induced protective proteins Bcl-xL and SOD2, and unlike STAT3 KO mice, cardiac miR-199a levels were not increased in SA mice. AII increased systolic blood pressure measured by telemetry in SA (124 ± 1 to 167 ± 3) and WT (122 ± 3 to 162 ± 3) mice to the same extent. AII increased cardiac levels of cytokines (pg/μg protein) associated with heart failure in both WT and SA mice, but significantly less so (P<0.05) in SA mice; IL-6, 13.6 ± 1.4 vs. 9.1 ± 0.6; TGFβ, 56 ± 4 vs. 38 ± 3 and MCP1 35 ± 2 vs. 22 ± 2. Compared to WT mice, hearts of SA mice showed signs of developing systolic dysfunction with AII as seen by a significant (P<0.05) reduction in ejection fraction (63.7 ± 7.1 to 51.7 ± 6.9) and fractional shortening (34.3 ± 4.9 to 26.4 ± 4.3). AII caused fibrosis in the left ventricle of both WT and SA mice characterized by cardiac myocyte loss and increased % collagen: WT+S, 5.59 ± 0.34; WT+AII, 15.70 ± 1.87; SA+S, 6.70 ± 0.40; SA+AII, 16.50 ± 1.91. In WT+AII mice there was a nonsignificant trend towards a loss of myofibrillar content of cardiac myocytes, but an increase in the mass of the myofibrils (IOD/myofibrillar area). In contrast, cardiac myocytes of SA+AII mice had a significant (P<0.001) % loss in myofibrils (5.71 ± 0.28) compared to SA+S (0.75 ± 0.07), WT+S (0.80 ± 0.06) and WT+AII (1.54 ± 0.10) mice. In addition, the mass of the myofibrils in SA+AII mice (6.01 ± 0.07) was significantly less (P<0.001) than those of SA+S mice (6.46 ± 0.04), although greater than WT+S (4.85 ± 0.06) or WT+AII (5.27 ± 0.08) mice. Our findings reveal that STAT3 transcriptional activity is important for proper morphology of the myofibrils of cardiac myocytes. Loss of STAT3 activity may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.


2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Abdelaziz Beqqali ◽  
Ingrid van Rijsingen ◽  
Inge van der Made ◽  
Stephanie van den Oever ◽  
Yigal Pinto

Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure due to systolic dysfunction. Mutations in the LMNA gene, which encodes the nuclear lamina proteins Lamin A and C, are the most common cause of familial DCM. Current treatment strategies to improve the prognosis are limited to implantable cardioverter-defibrillator and heart transplantation. Patients with LMNA-related DCM are treated in accordance with international guidelines for the management of heart failure with little consideration of the possible influence of the etiology on the response to treatment. Recent studies suggest that this might result in inappropriate therapy in some patients. The influence of genetic factors in determining the response (and timing) of drug therapy is largely unstudied in DCM. Therefore, our aim is to determine the efficacy of existing heart failure drugs in preventing or delaying LMNA-related DCM. We used a well-established mouse model of Lamin A/C mimicking human LMNA-related DCM. Mice heterozygous for the Lmna mutant gene (n=20 per group) were treated with Metoprolol (β-blocker) or Enalapril (ACE-inhibitor) before the onset of DCM and were functionally evaluated by serial echocardiography and ECG until 75 weeks of age. Hearts were harvested for histological analysis and molecular characterization. Interestingly, the experimental group treated with Enalapril had a preserved overall cardiac function comparable to wildtype mice. Mice treated with Metoprolol however, displayed progressive heart failure, and an aggravated cardiac function compared to untreated Lmna +/- mice. Both the beneficial effects of Enalapril in preventing development of systolic dysfunction as well as the detrimental effect of Metoprolol were confirmed by expression of molecular stress markers and degree of cardiac fibrosis. Our results suggest that Enalapril is effective in preventing Lmna+/- induced cardiomyopathy in mice. Strikingly, Metoprolol increases cardiac dysfunction and stress in Lmna+/- mice. Further studies will determine whether Enalapril is also effective in preventing LMNA-related DCM in patients, and whether omitting Metoprolol from the standard cocktail of prescribed heart failure medicine is beneficial for LMNA patients.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Inazumi ◽  
K Kuwahara ◽  
Y Kuwabara ◽  
Y Nakagawa ◽  
H Kinoshita ◽  
...  

Abstract Background We previously demonstrated that a transcriptional repressor, neuron restrictive silencer factor (NRSF), maintains normal cardiac function and electrical stability. Transgenic mice expressing a dominant-negative mutant of NRSF in their hearts (dnNRSF-Tg) exhibit systolic dysfunction with cardiac dilation and premature death due to lethal arrhythmias like human dilated cardiomyopathy (DCM). Underlining mechanisms remain to be elucidated, however. Purpose We studied underling mechanisms by which NRSF maintains normal cardiac function to identify novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSFcKO) and confirmed that cardiac phenotypes of NRSFcKO are similar to those of dnNRSF-Tg. cDNA microarray analysis revealed that cardiac gene expression of GNAO1 that encodes Gαo, a member of inhibitory G protein Gαi family, is increased in both dnNRSF-Tg and NRSFcKO ventricles. We confirmed that GNAO1 is a direct target of NRSF through ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay. In dnNRSF-Tg, pharmacological inhibition of Gαo with pertussis toxin improved systolic dysfunction and knockdown of Gαo by crossing with GNAO1 knockout mice improved not only systolic function but also frequency of ventricular arrhythmias and survival rates. Electrophysiological and biochemical analysis in ventricular myocytes obtained from dnNRSF-Tg demonstrated that genetic reduction of Gαo ameliorated abnormalities in Ca2+ handling, which include increased current density in surface sarcolemmal L-type Ca2+ channel, reduced content of sarcoplasmic reticulum Ca2+ and lowered peak of Ca2+ transient. Furthermore, genetic reduction of Gαo attenuated increased phosphorylation levels of CAMKII in dnNRSF-Tg ventricles, which presumably underlies the improvement in Ca2+ handling. In addition, we identified increased Gαo expression in ventricles of heart failure model mice induced by transverse aortic constriction and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gαo ameliorated cardiac dysfunction. Figure 1 Conclusions We found that increased expression of Gαo, induced by attenuation of NRSF-mediated repression, plays a crucial role in the progression of cardiac dysfunction and lethal arrhythmias by evoking Ca2+ handling abnormality. These data demonstrate that Gαo is a potential therapeutic target for heart failure.


2020 ◽  
Vol 10 (4) ◽  
pp. 243-256
Author(s):  
Ying-Kuang Lin ◽  
Chih-Chin Kao ◽  
Chi-Ho Tseng ◽  
Ching-En Hsu ◽  
Yi-Je Lin ◽  
...  

Background: Although the dynamics of blood pressure (BP) during dialysis provide information related to the control system, the prognosis and relationships between temporal changes in intradialytic hemodynamic regulation, BP, and decreased cardiac function remain largely unclear. Methods: Hemodynamic parameters, including heart rate (HR), stroke volume (SV), cardiac index, and systemic vascular resistance index, were recorded using a noninvasive hemodynamic device on a beat-by-beat basis in 40 patients on dialysis who were divided into three groups, i.e., those with and without BP lability and those with heart failure (HF). Statistical measurements, including mean, standard deviation, coefficient of variation (CV), and index of nonrandomness of each hemodynamic parameter were derived from the three different phases divided equally during dialysis and compared using 3×3 two-way mixed-model analysis of variance to determine the effects of the different stages of hemodialysis (HD), cardiac function, and intradialytic changes in BP on the hemodynamic parameters. In addition, multivariate Cox regression was performed to determine the association between the changes in the derived parameters and BP lability. Results: The average SV tended to decrease during HD in all groups (p = 0.041). A significant decrease was observed in the CV of SV between the first two stages of HD in patients with labile BP and HF when compared to those without labile BP (p = 0.037). Significant interactions between group and stage of the index of nonrandomness for HR were also noted; this index was significantly higher in patients without labile BP than in those with labile BP or HF (p = 0.048). A higher difference between the early and middle stages of HD for nonrandomness indexes of HR was an independent predictor of reduced BP lability during HD (HR = 0.844, 95% confidence interval 0.722–0.987, p = 0.034). Conclusions: Increases in the CV of SV and the index of nonrandomness for HR during early-stage HD in response to decreased SV may be associated with better BP control during HD. This finding suggests that patients with more structurally meaningful hemodynamic control have a more favorable cardiovascular outcome.


Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1896 ◽  
Author(s):  
Takao Kato ◽  
Takatoshi Kasai ◽  
Akihiro Sato ◽  
Sayaki Ishiwata ◽  
Shoichiro Yatsu ◽  
...  

Astaxanthin has strong antioxidant properties. We conducted a prospective pilot study on heart failure (HF) patients with left ventricular (LV) systolic dysfunction to investigate improvements in cardiac function and exercise tolerance in relation to suppression of oxidative stress by 3-month astaxanthin supplementation. Oxidative stress markers—serum Diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP), and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) concentrations, LV ejection fraction (LVEF), and 6-min walk distance (6MWD) were assessed before and after 3-month astaxanthin supplementation. Finally, the data of 16 HF patients were analyzed. Following 3-month astaxanthin supplementation, dROM level decreased from 385.6 ± 82.6 U.CARR to 346.5 ± 56.9 U.CARR (p = 0.041) despite no changes in BAP and urinary 8-OHdG levels. LVEF increased from 34.1 ± 8.6% to 38.0 ± 10.0% (p = 0.031) and 6MWD increased from 393.4 ± 95.9 m to 432.8 ± 93.3 m (p = 0.023). Significant relationships were observed between percent changes in dROM level and those in LVEF. In this study, following 3-month astaxanthin supplementation, suppressed oxidative stress and improved cardiac contractility and exercise tolerance were observed in HF patients with LV systolic dysfunction. Correlation between suppression of oxidative stress and improvement of cardiac contractility suggests that suppression of oxidative stress by astaxanthin supplementation had therapeutic potential to improve cardiac functioning.


2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ippei Shimizu ◽  
Tohru Minamino ◽  
Yohko Yoshida ◽  
Taro Katsuno ◽  
Issei Komuro ◽  
...  

Several clinical studies have shown that insulin resistance is prevalent among patients with impaired cardiac function and that systemic insulin resistance is the risk factor for the development of heart failure; however, underlying mechanisms have not been fully elucidated. We have previously reported that increased p53 level in adipose tissue is crucially involved in adipose inflammation and insulin resistance during pressure overload. Here we show that . Pressure overload increased sympathetic activity and promoted lipolysis in adipose tissue. Accelerated lipolysis resulted in increases of reactive oxygen species and DNA damage, leading to up-regulation of adipose p53. This up-regulation activated the NF-kappaB pathway and induced adipose inflammation and insulin resistance. Genetic disruption of adipose p53 markedly attenuated adipose inflammation and metabolic abnormalities associated with heart failure. We also observed that cardiac function and survival in the chronic phase of heart failure were significantly better in adipose tissue p53-deficient mice than control littermates. Pharmacological inhibition of adipose p53 after imposing pressure overload also improved cardiac dysfunction as well as insulin resistance in the chronic phase of heart failure. These results suggest that inhibition of adipose inflammation is a potential target for treating metabolic abnormalities and systolic dysfunction in patients with heart failure.


Autoimmunity ◽  
2008 ◽  
Vol 41 (6) ◽  
pp. 473-477 ◽  
Author(s):  
Azra Isic ◽  
Margareta Scharin Täng ◽  
Espen Haugen ◽  
Michael Fu

2019 ◽  
Vol 13 (1) ◽  
pp. 46-48
Author(s):  
Miguel Alejandro Rodriguez-Ramos

Diabetes is a major risk factor for heart disease. Diabetic cardiomyopathy is a long-lasting process that affects the myocardium in patients who have no other cardiac conditions. The condition has a complex physiopathology which can be subdivided into processes that cause diastolic and/or systolic dysfunction. It is believed to be more common than reported, but this has not been confirmed by a large study. Diagnosis can involve imaging; biomarkers cannot be used to identify diabetic cardiomyopathy at an early stage. In people with diabetes, there should be a focus on prevention and, if diabetic cardiomyopathy develops, the objective is to delay disease progression. Further studies into identifying and managing diabetic cardiomyopathy are essential to reduce the risk of heart failure in people with diabetes.


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